Colorectal cancer affects a significant number of individuals in most industrialized countries around the world. It alone is responsible for an annual death toll in the United States of approximately 56,000 people. Many patients present with advanced disease with which the outcome is poor and mortality high even with the most advanced treatment options available. Based on a better understanding of the biology of the large intestine and the specific signaling pathways affected during colorectal carcinogenesis, investigators are evaluating better ways to detect and prevent this disease. Along these lines, we have found that a particular enzyme, cyclooxygenase-2 (COX-2), is upregulated in colorectal cancer tissue and in pre-malignant adenomas. Our previous funding cycle was devoted to understanding the mechanisms, which led to increased expression of the COX-2 gene and the role this gene played in gut biology and carcinogenesis. Now we propose to evaluate the downstream signaling pathways affected by increased COX-2 activity. Cyclooxygenase is a key enzyme in the production of prostaglandins, which are bioactive lipids that activate several downstream signaling pathways. Others have shown that overexpression of COX-2 in the skin or breast leads to a dramatic increase in risk for skin or breast carcinoma. We have shown in preliminary data that PGE2 can lead to pro-neoplastic effects in a number of situations. We propose the following specific alms to investigate this problem further: 1) To determine the mechanism(s) by which COX-2 derived PGE2 regulates the motility and invasiveness of colorectal carcinoma cells. 2) To delineate the role of the nuclear PGI2 receptor, PPARd, in the development of colorectal cancer. 3) To determine the relative contribution of COX-2 expressed in malignant epithelial cells versus the surrounding stroma (host) in promoting colorectal cancer. This work will help to delineate additional important targets for treatment and/or prevention of colorectal cancer. It is becoming clear that just targeting one single molecule will not be as effective as needed to have a significant impact on this disease.